| Part I THE RELEVANT STUDY BETWEEN SINGLE NUCL?EOTIDE POLYMERPHISMS AND SUSCEPTIBILITY AND RISK FACTOR OF ACUTE MYOCARDIAL INFARCTIONBACKGROUND:Acute myocardial infarction (AMI), characterized by dangerous pathogenic conditions and high fatality, is a serious complication and major cause of death of coronary heart disease (CHD). The prevalence of AMI tended to increase and its incidence showed younger trend. Recently, AMI has become one of the most dangerous diseases that seriously affected the quality of life of our citizens with an increasing burden of economy and medicine. With the development and adaptation of genetic sequencing technology, single nucleotide polymorphisms (SNPs) have been to a new generation of molecular genetic markers and have identified lots of genetic loci associated disease susceptibility. It has been well documented that SNPs in 9p21 was associated with AMI. The low density lipoprotein receptor (LDLR) gene and proprotein convertase subtilisin/kexin type 9 (PCSK9) genes may be the risk factors for AMI. The mutation and expression disorders of cyclin-dependent kinase inhibitor 2A/2B (CDKN2A/2B) gene can be affect cell cycle, proliferation and apoptosis, and other functions directly or indirectly, resulting in atherosclerosis. Moreover, the upregulation of chemokine (C-X-C motif) ligand 12 (CXCL12) genes can promote CXCL12 migration and improve the ischemia anoxic myocardial cells subsequently. The association of LDLR rs 1122608, PCSK9 rs11206510, CDKN2A/2B rs4977574 and CXCL12 rs1746048 SNPs with AMI have been reported in the European and American populations. However, little was known about this association in Chinese population, especially in population from Guangxi province. Therefore, the understanding of the association of these loci with susceptibility and risk factors for AMI may help to know the genetic characteristics and further provide new approach to screen high-risk population and prevention for AMI.OBJECTIVE:The present study was undertaken to detect the associations of LDLR rs1122608, PCSK9 rs11206510, CDKN2A/2B rs4977574, CXCL12 rs1746048 SNPs and gene-risk factors interactions with the susceptibility for AMI.METHOD:Totals of 600 cases of blood samples were obtained from patients with AMI (n=300) and an equal number of blood samples from normal people (n=300) at the same period were collected as normal group. All of them were from Guangxi province. Genotyping of LDLR rs1122608, PCSK9 rs11206510, CDKN2A/2B rs4977574, CXCL12 rs1746048 SNPs were performed using polymerase chain reaction and restriction fragment length polymorphism (PCR-RFLP). Information on medical history, dietary structure, lifestyle factors, height, weight, waist circumference, blood pressure, and family history were collected with standardized questionnaires. The two group were compared the difference of genotypic and allelic frequencies and explored the associations between the four SNPs and susceptibility for AMI. Non-conditional binary logistic regression analysis was performed to assess the relationship of risk factors such as sex, age, cigarette smoking, alcohol consumption, body mass index, lipid levels, and genotypes with AMI.RESULTS1. Comparison of generalized features:the values of mean age (61.67± 10.43 vs 58.49±10.54) and body mass index (BMI,23.76±3.11 vs 22.66± 3.15) were higher in AMI group than in normal group. The numbers (percentages) of subjects who smoked cigarettes and consuming alcohol were 144 (48.00),74 (24.67%) in AMI group,75 (25.00%),60 (20.00%) in normal group, respectively. Both the numbers of subjects who smoked cigarettes and consuming alcohol were higher in AMI group than normal group. There was no significant difference in the sex structure between the two groups.2. Comparison of lipid levels:The levels of serum total cholesterol (TC), triglyceride (TG), and low-density lipoprotein cholesterol (LDL-C) were 5.20± 0.95 mmol/L,1.66±1.13 mmol/L, and 3.71±0.92 mmol/L in AMI group; 4.97 ±1.05 mmol/L,1.45±1.11 mmol/L, and 2.89±0.87 mmol/L in normal group; respectively. There was significant difference in the levels of serum TC, TG, and LDL-C. AMI group had higher levels of serum TC, TG, and LDL-C than normal normal group (P< 0.05 for all). However, the serum high-density lipoprotein cholesterol (HDL-C) levels were lower in AMI group than in normal group (1.08±0.26 mmol/L vs 1.36±0.25 mmol/L, P< 0.001).3. Comparison of the genotypic and allelic frequencies:(1) LDLR rs 1122608 SNPs:The wild-type GG genotype and G allele frequency respectively was 23.67% and 48.67% in AMI group, lower than 82.67% and 89.83% of normal group; The frequencies of mutations GT, TT, GT+TT genotypes and T allele respectively were 50.00%,26.33%,76.33% and 51.33% in AMI group, higher than 14.33%,3.00%,17.33% and 10.17% of the normal population group in normal group. Significant differences in both genotypic and allelic frequencies between AMI and normal group were detected (P< 0.001 for all). (2) CDKN2A/2B rs4977574 SNPs:The wild-type AA genotype and A allele frequency respectively was 38.00% and 60.67% in AMI group, higher than 16.33% and 44.67% of normal group; The frequencies of mutations AG, GG, AG +GG genotypes and G allele respectively were 45.33%,16.67%,62.00% and 39.33% in AMI group, lower than 56.67%,27.00%,83.67% and 55.33 of the normal population group in normal group. There were significant differences in both genotypic and allelic frequencies between AMI and normal group (P< 0.01 for all). (3) PCSK9 rs11206510 SNPs:The wild-type TT genotype and T allele frequency respectively was 79.67% and 87.83% in AMI group, lower than 87.34% and 93.50% of normal group; The frequencies of mutations TC, CC, TC +CC genotypes and C allele respectively were 16.33%,4.00%,20.33% and 12.17% in AMI group, higher than 12.33%,0.33%,12.66% and 6.50% in normal group. There were significant differences in both genotypic and allelic frequencies between AMI and normal group (P< 0.05 for all). (4) CXCL12 rs1746048 SNPs:In AMI group and the normal group, the frequencies of CC, CT, TT and CT+TT genotype respectively were 55.67%,43.33%,1.00%, 44.33% and 50.00%,50.00%,0.00%,50.00%; C and T allele frequencies respectively were 77.33%,22.67% and 75.00%,25.00%; no significant difference in genotypic and allelic frequencies between AMI and normal group was detected (P> 0.05).4. Risk factors:Non-conditional binary logistic regression analysis showed that serum HDL-C levels, rs 1122608 SNPs, age,and cigarette smoking were strongly correlated with the risk of AMI and the ORs were 55.56 (1/0.018), 19.23 (1/0.052),8.62 (1/0.116),7.87 (1/0.127),4.76 (1/0.210), and 4.59 (1/0.218), respectively. There were significant differences in the ORs between AMI group and normal group (P< 0.001 for all). The rs4977574 SNPs, sex, and BMI were middling correlated with the risk of AMI and the ORs were 2.067, 0.473, and 0.524. There were significant differences in the ORs between AMI group and normal group (P< 0.05-0.001). However, no significant differences in the correlations of TC, TG, LDL-C, consuming alcohol, rs11206510 SNPs, and rs11206510 SNPs with the risk of AMI between the two groups (P> 0.05 for all).CONCLUSION:1. The genotypic and allelic frequencies of LDLR rs1122608 SNPs were significantly different between AMI group and normal group. The mutant GT, TT, GT+TT genotypes were positively correlated with the risk of AMI. The T allele carriers had higher risk of AMI morbidity.2. The genotypic and allelic frequencies of CDKN2A/2B rs4977574 SNPs were significantly different between AMI group and normal group. The mutant AG, GG, AG+GG genotypes were associated with reduced susceptibility of AMI and the G allele was a protective gene for AMI.3. Significant differences were detected in the genotypic and allelic frequencies of PCSK9 rs11206510 SNPs between AMI group and normal group. The mutant TC, CC, TC+CC genotypes were positively correlated with the risk of AMI. The C allele carriers had higher risk of AMI morbidity.4. There were no differences of genotypic and allelic frequencies in CXCL12 rs1746048 SNPs between the two groups.5. Serum HDL-C levels, LDLR rs1122608 SNPs, age, and cigarette smoking were strongly correlated with the risk of AMI.Part II THE RELEVANT STUDY BETWEEN SINGLE NUCLE?OTIDE POLYMERPHISMS AND CLINICAL CHARA?CTERISTICS OF ACUTE MYOCARDIAL INFARCTIONBACKGROUND: Acute myocardial infarction(AMI) was a serious disease associated with come on urgent, high mortality. It is the key that early rapid diagnosis and timely thrombolysis or percutaneous coronary intervention(PCI) therapy for treatment of AMI effectively. The companion for the management of ST segment elevation acute myocardial infarction was put forward by European Society of Cardiology in 2012. The companion suggested that the patients should be given thrombolytic therapy in 30 minutes or PCI in 90 minutes for which can significantly reduce the mortality and improve prognosis. Recently, along with the development and application of genome-wide association study(GWAS), the international hapmap project, and high-throughput SNPs classification technology, more and more studies have focused on molecular genetics of AMI and put major concentration in screening of susceptibility genes. However, little was known about the association between susceptive SNPs and clinical features of AMI. It has reported thatLDLR rs 1122608, PCSK9 rsl 1206510, CXCL12 rsl746048, and CDKN2A/2B rs4977574 SNPs were correlated with susceptibility of AMI in European and American populations. However, there were hardly any previous studies pre-’sented the direct relationship between these SNPs and susceptibility of AMI in humans. The discovery of the correlation between rsl 122608, rs4977574,rsl 1206510, and rsl746048 SNPs by genotyping and AMI(typical symptoms,early diagnosis, serious complications, and infarction location) may help to develop better early diagnosis and treatment.OBJECTIVE: The present study was undertaken to detect the correlations between LDLR rsl 122608, CDKN2A/2B rs4977574, PCSK9 rsl 1206510, and CXCL12 rsl 746048 SNPs and clinical features of AMI, and to further investigate the association of these SNPs with typical symptoms, early diagnosis,serious complications, and infarction location of AMI.METHODS: Genotyping have been performed in 300 cases of AMI patients formerly and then the 300 cases were regrouped.(1) They were divided into two groups according to typical symptoms: typical symptoms group(n=78) and atypical symptoms group(n = 222);(2) They were divided into four subgroups according to diagnosis time(DT): DT < 2h group(n = 40),2h < DT< 6h group(n = 119),6h < DT < 12 h group(n = 116), and DT > 12 h group(n=25);(3) They were divided into six subgroups according to infarction location:extensive anterior wall group(n = 141), inferior wall group(n = 97), anteroseptal wall group(n = 18), side wall group(n = 7), right ventricular group(n =13), and muti_vessel lesion group(n = 24);(4) They were divided into two subgroups according to serious complications: no serious complications group(n = 275) and serious complications group(n = 25). Comparison of the genotypic and allelic frequencies of LDLR rsl 122608, CDKN2A/2B rs4977574,PCSK9 rsl 1206510, and CXCL12 rs 1746048 SNPs were performed among the subgroups.RESULTS1.SNPs and the diagnosis time: There were significant differences in the genotypic frequencies of the four SNPs among the subgroups(P < 0.05 for all).However, no significant differences in the genotypic allelic of the four SNPs among the subgroups {P > 0.05 for all). The frequencies of GT genotypes of LDLR rsl 122608 SNPs were the highest in DT < 2h group(52.50%), higher than those of the others groups {P < 0.001). The frequencies of AG genotypes of CDKN2A/2B rs4977574 SNP was the highest in 2h < DT < 6h(68.91%) higher than those of the others groups(P < 0.001). The frequencies of CC genotypes of CXCL12 rsl746048 SNP was the highest in 2h < DT < 6h(61.34%), higher than those of the others groups(P < 0.05). The frequencies of TT genotypes of PCSK9 rsl 1206510 SNP was the highest in 6h < DT < 12h(82.76%) higher tiian those of the others groups {P < 0.05).2.SNPs and serious complications: The frequencies of AG genotypes of DKN2A/2B rs4977574 SNPs was the highest in serious complications group(46.55%), higher than those of the others groups {P < 0.05). There were no significant differences in the frequencies of AG + GG genotypes and allele frequencies between the two groups(P > 0.05). The frequencies of CT genotypes of CXCL12 rsl746048 SNPs was the highest in serious complications group(68.00%), higher than those of the others groups(P < 0.05); The frequencies of CT + TT genotype and T allele of CXCL12 rsl746048 SNPs respectively was 72.00% and 38.00% of serious complications group, higher than 42.82% and 21.27 of no serious complications group(P < 0.01 for each).There were no significant differences in the genotypic and allelic frequencies ofLDLR rs1122608 and PCSK9 rs11206510 between the two groups(P〉0.05 for all).3, No significant differences were detected in the genotypic and allelic frequencies of the four SNPs between the two subgroups according to typical symptoms, and among the six subgroups according to infarction location(P >0.05 for all).CONCLUSIONS1.The GT + TT genotypes of LDLR rs1122608 SNP, AG + GG genotypes of CDKN2A/2B rs4977574 SNP, and CC genotype of CXCL12 rsl746048 SNPs were positively correlated with the early diagnosis(DT < 6h) of AMI.2.There was a negative correlation between AG genotypes of CDKN2A/2B rs4977574 SNPs and AMI associated with severe complications; but there were a positive correlation between CT + TT genotype and T allele of CXCL12 rsl 746048 SNPs and AMI associated with severe complications.3.There were no evidences to support a correction of LDLR rsl 122608,CDKN2A/2B rs4977574, PCSK9 rsl 1206510, and CXCL12 rsl746048 SNPs with typical symptoms and infarction location; respectively. |
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